阻断CXCR4+ CD4+ T细胞通过调节Rho-GTPase/NF-κB信号轴重编程treg介导的免疫抑制。

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Canhui Cao, Miaochun Xu, Ting Peng, Xiaojie Liu, Shitong Lin, Yashi Xu, Tian Chu, Shiyi Liu, Ping Wu, Bai Hu, Wencheng Ding, Li Li, Ding Ma, Peng Wu
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引用次数: 0

摘要

背景:虽然临床试验表明CXCR4拮抗剂可以增强癌症免疫治疗的疗效,但CXCR4调节肿瘤微环境的分子机制尚不清楚。我们最近发现CXCR4是癌症中耗尽CD8+ T细胞表型的调节因子。在这里,我们研究了它在协调肿瘤内调节性T (Treg)细胞介导的免疫抑制中的作用。方法:我们对来自泛癌组织的单细胞RNA-seq数据集进行了荟萃分析,以表征CD4+ T细胞中CXCR4的表达模式。使用CXCR4拮抗剂和条件敲除小鼠(Cxcr4flox/flox, LckCre),我们在体内抑制Treg表型。通过宫颈癌小鼠模型的单细胞转录组学和单细胞ATAC-seq、磷酸化蛋白质组学和ChIP-seq分析,我们阐明了CD4+ T细胞中CXCR4阻断如何通过调节Rho-GTPase/NF-κB信号轴抑制活化的Treg表型。我们进一步整合RNA-seq数据、临床试验数据集(NCT02826486和NCT04516616)和人类类器官模型,以验证CXCR4抑制在增强抗肿瘤免疫治疗中的治疗潜力。结果:多种癌症中CD4+ T细胞的单细胞转录组学显示CXCR4的表达与Treg细胞的发育轨迹有关。药理和遗传抑制CXCR4可抑制宫颈癌和乳腺癌中的Treg表型。机制上,磷酸化蛋白组学和ChIP-seq分析揭示了阻断CXCR4+ CD4+ T细胞通过调节Rho-GTPase/NF-κB信号轴减少活化的Treg表型。单细胞转录组学和多组学分析表明,阻断CXCR4+ CD4+ T细胞通过重编程treg介导的免疫抑制促进免疫治疗。此外,临床试验数据和人类宫颈癌类器官证实,阻断CXCR4通过降低Treg表型来增强抗肿瘤免疫治疗。结论:我们的研究强调了CXCR4通过调节Rho-GTPase/NF-κB信号轴在treg介导的免疫抑制中发挥的关键作用,提示了将CXCR4阻断与T细胞靶向免疫治疗相结合的可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Blocking CXCR4+ CD4+ T cells reprograms Treg-mediated immunosuppression via modulating the Rho-GTPase/NF-κB signaling axis.

Background: While clinical trials have shown that CXCR4 antagonists can enhance the efficacy of cancer immunotherapy, the molecular mechanisms by which CXCR4 modulates the tumor microenvironment remain poorly understood. We recently identified CXCR4 as a regulator of exhausted CD8+ T cell phenotypes in cancer. Here, we investigate its role in orchestrating regulatory T (Treg) cell-mediated immunosuppression within tumors.

Methods: We conducted meta-analyses of single-cell RNA-seq datasets from pan-cancer tissues to characterize CXCR4 expression patterns in CD4+ T cells. Using CXCR4 antagonists and conditional knockout mice (Cxcr4flox/flox, LckCre), we inhibited Treg phenotypes in vivo. Through single-cell transcriptomics and single-cell ATAC-seq of the cervical cancer mouse model, phosphoproteomics, and ChIP-seq analyses, we elucidated how CXCR4 blockade in CD4+ T cells suppresses activated Treg phenotypes by modulating the Rho-GTPase/NF-κB signaling axis. We further integrated RNA-seq data, clinical trial datasets (NCT02826486 and NCT04516616), and human organoid models to validate the therapeutic potential of CXCR4 inhibition in enhancing antitumor immunotherapy.

Results: Single-cell transcriptomics of CD4+ T cells across multiple cancers revealed CXCR4 expression was associated with Treg cell developmental trajectories. Pharmacological and genetic inhibition of CXCR4 inhibited Treg phenotypes in cervical cancer and breast cancer. Mechanistically, phosphoproteomics and ChIP-seq analyses unveiled that blocking CXCR4+ CD4+ T cells reduced activated Treg phenotypes by modulating the Rho-GTPase/NF-κB signaling axis. Single-cell transcriptomic and multi-omic analyses demonstrated that blocking CXCR4+ CD4+ T cells promoted immunotherapy via reprogramming Treg-mediated immunosuppression. Furthermore, clinical trial data and human cervical cancer organoids confirmed that blocking CXCR4 enhances antitumor immunotherapy by reducing Treg phenotypes.

Conclusions: Our study highlights the crucial role of CXCR4 in deriving Treg-mediated immunosuppression via regulating the Rho-GTPase/NF-κB signaling axis, informing the potential of combining CXCR4 blockades with T cell-targeted immunotherapies.

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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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